国际上研究报道，胞苷脱氨酶CDA是导致修饰胞苷5hmdC、5fdC对肿瘤细胞造成杀伤作用的关键酶。CDA对5hmdC、5fdC脱氨产生5hmdU和5fdU，其转变成5hmdUTP和5fdUTP后掺入基因组DNA，造成DNA损伤和细胞死亡。.而我们通过筛选发现5hmdC、5fdC对Raji、SEM等不表达CDA的细胞依然有杀伤作用，提示CDA不是调控5hmdC、5fdC代谢的唯一途径。据研究报道，我们猜测胞苷激酶DCK和脱氧胞苷酸脱氨酶DCTD可能在调控5hmdC、5fdC代谢并对细胞造成杀伤作用中起关键作用。在此项目中，我们将通过遗传、生化实验进一步探究5hmdC、5fdC在肿瘤细胞中的代谢途径，以及其抑制细胞增殖的作用机制；并通过裸鼠皮下成瘤实验探究5hmdC和5fdC以及与阿糖胞苷联合用药对肿瘤的抑制效果。此工作为将5hmdC、5fdC开发成新的抗肿瘤药物奠定基础和提供思路。

According to an international study，cytidine deaminase CDA is the key enzyme that leads to cell lethality after exposure to 5hmdC or 5fdC. CDA converts 5hmdC and 5fdC into variants of uridine that are incorporated into DNA, resulting in accumulation of DNA damage, and ultimately, cell death. . However, by screening cancer cell lines for growth defects after exposure to 5hmdC or 5fdC, we unexpectedly found that 5hmdC and 5fdC lead to a subset of cell lines to cell lethality, which lack expression of CDA, suggesting that CDA is not the only metabolic enzyme of 5hmdC and 5fdC. According to thorough literature review, we hypothesize that cytidine kinase DCK and deoxycytidylate deaminase DCTD may play a key role in regulating 5hmdC and 5fdC metabolism and causing cell lethality.. In the proposed project, we attempt to dissect the metabolic mechanisms of 5hmdC and 5fdC in tumor cells，and the mechanism of cell death after exposure to 5hmdC or 5fdC by genetic and biochemical approaches. Then, we will identify the therapeutic potential of 5hmdC and 5fdC alone or in combination with cytarabine through mouse experiments, which will lay a foundation for the development of 5hmdC and 5fdC into new anti-tumor drugs.